Heterocyclic compounds and process for producing same



United States Patent:

HETEROCYCLIC COIHPOUNDS AND PRUiIESS FOR PRODUCING SAME Karl Holfmannand Ernst Urech, Binningen, Switzerland,

assignors to Ciba Pharmaceutical Products Inc., Sum= mit, N. J.

No Drawing. Application May 22, 1957 Serial No. 660,742

cation, Serial No. 489,305, filed February 18, 1955, now abandoned.

This invention relates tolo-(tertiary-aminoalkyl)-lloxo-dibenzo[b:f]-thia-[l]-aza-[4]cycloheptadiene [2:6]- compounds having the general formula:

and salts, such as acid addition salts or quaternary ammonium saltsthereof. A in the above general formula represents a lower alkyleneradical and R and R represent, interchangeably, lower alkyl orcycloalkyl radicals, and when taken together, lower alkylene or lowermonooxyaalkylene radicals, preferably those containing 4 to 5 carbonatoms. The positions 1 to 4 and 6 to 9 may be unsubstituted orsubstituted, that is to say, R and R may represent, interchangeably,hydrogen, halogen, i. e. chloro, bromo, fluoro or iodo; amino; loweralkyl or lower alkoxy groups.

The tertiary aminoalkyl radical, of which the alkylene chain may bestraight or branched, is preferably a tertiary amino-lower alkylradical. The tertiary amino group is more especially an amino groupdisubstituted by alkyl and/or cycloalkyl radicals or an amino groupdisubstituted by an alkylene radical which may, if desired, beinterrupted by :1 hereto atom such as oxygen. Such aminoalkyl radicalsare, for example, dimethylamino-, diethylamino-, pyrrolidino-,piperidino-, or morpholinoethyl, -propyl, -isopropyl, -butyl, -isobutylor -pentyl groups.

As quaternary ammonium salts there may be mentioned, more especially,lower alkyl ammonium salts, for example, lower alkyl ammonium halides,e. g., methyl, ethyl, propyl and butyl ammonium chlorides.

These new basically substituted heterocyclic compounds which comprisethe invention possess an antihistaminic effect and are useful asantihistamines. They can be administered in any suitable manner, forexample orally, in combination with an adjuvant as a carrier tofacilitate the administration thereof.

The new compounds are obtained by introducing into an 1 l-oxo-dibenzo-[b:f]-thia-[l]-aza-[4]-cycloheptadiene- [2:6]-compound, which isunsubstituted in the 10-posi tion, a tertiary aminoalkyl radical intothe 10-position, and, if desired, converting the base so obtained intoan acid addition salt or a quaternary ammonium salt thereof. Theintroduction of this radical can be carried out for example, by reactingthe compound unsubstituted in 10-position, for example in the form of ametal salt 2,852,510 Patented Sept. 16, 1958 thereof or in the presenceof a condensing agent, especial- -ly one which is capable of forming ametal salt therewith, such as an alkali metal or alkaline earth metal,for example, sodium, lithium, calcium or an amide, hydride, hydrocarboncompound or alcoholate thereof, for example, sodamide, sodium hydride,lithium butyl, potassium phenyl, lithium phenyl, potassium tertiarybutylate or potassium tertiary amylate, with a reactive ester of atertiary aminoalkanol. Reactive esters, are especially those of stronginorganic or organic acids, such as bydrohalic acids, e. g. hydrochloricacid or organic sulfonic acids, such as paratoluene sulfonic acid.

The preparation of quaternary ammonium salts of a free tertiary amine soobtained is carried out, for example, by reaction with an alkyl halide,dialkyl sulfate or sulfonic acid alkyl ester.

Depending on the conditions used the new compounds are obtained in theform of their bases, acid addition salts, or quaternary ammonium salts.From the salts there can be obtained in known manner the free amines orammonium bases. From the free amines and ammonium bases, salts can beobtained by reaction with acids which are suitable for the formation oftherapeutically useful or non-toxic salts, for example, hydrohalicacids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,malic acid, methane sulfonic acid, ethane sulfonic acid, hydroxyethanesulfonic acid, benzene or toluene sulfonic acid or therapeuticallyactive acids.

The starting materials, namely 11-oxo-dibenzo-[b:f]-thia-[l]-aza-[4]-cycloheptadiene-[2 6] compounds which are unsubstitutedin the l0-p0sition are new. In general they are prepared byintramolecularly condensing by heating in the absence of an acidcondensing agent N-unsubstituted 2-amino-diphenylsulfide-2'-carboxylicacids or their functional derivatives, e. g. esters with lower alkanols.The novel intermediates and process for their manufacture are describedbelow.

The new compounds are useful as medicaments, for example, in the form ofpharmaceutical preparations, which contain the new compound or a saltthereof in admixture with a pharmaceutical organic or inorganic solid orliquid carrier suitable for enteral, parenteral or topicaladministration. For making up the preparation there can be employedsubstances which do not react with the new compounds such, for example,as water, gelatine, lactose, starches, magnesium stearate, talc,vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleumjelly, cholesterol or another known carrier for medicaments. Thepharmaceutical preparations may be, for example, in the form of tablets,dragees, salves, creams or in liquid form as solutions, suspensions oremulsions. If desired, they may be sterilized and/ or contain auxiliarysubstances, such as preserving agents, stabilizing agents, wetting oremulsifying agents, salts for varying the osmotic pressure or buffers.They may also contain other therapeutically useful substances. Thepreparations are obtained by the usual methods employed in formulatingpharmaceutical dosage forms.

The following examples illustrate the invention, the parts being byweight unless otherwise stated and the relationship of parts by weightto parts by volume being the same as that of the gram to the cubiccentimeter:

EXAMPLE 1 22.7 parts of1l-oxo-dibenzo-[b:f]-thia-[ll-aza-[4lcycloheptadiene-[2:6] and 5 partsof sodamide are heated in 400 parts by volume of xylene at the boiluntil the evolution of ammonia ceases. A solution of 20 parts offl-diethylamino-ethyl chloride in xylene is run in in the course of 2hours, and the whole is heated for a further 3 2 hours at 120135 C.After being cooled to about 80 C., the reaction mass is then filteredwith suction and the xylene is distilled off in vacuo. The residue isdissolved in dilute hydrochloric acid, the solution is extracted withether, and the aqueous solution is mixed with alkali.

The base which separates is dissolved in ether, the ethereal solution isdried over potassium carbonate and evaporated. By distillation there isobtained in good yield a fraction boiling at l65-170 C. under 0.18 mm.pressure in the form of a pale yellow oil. It is10-(fi-diethylamino-ethyl)- 1l-oxo-dibenzo-[bzf]-thia-[11-aza [4]cycloheptadiene- [2:6] of the formula ner there can be obtained othersalts such as the hydrobromide, phosphate, sulfate, oxalate and thelike.

EXAMPLE 2 22.7 parts of 1l-oxo-dibenzo-[bzf]-thia-[ll-aza-[4lcycloheptadiene-[ZzG] and 5 parts of sodamide are heated with250 parts by volume of dioxane for 90 minutes at the boil, during whichammonia is evolved. A solution of 13 parts of fl-dimethylamino-ethylchloride in dioxane is then added in the course of one hour at the boil,and the mixture is boiled for a further 2 hours. After the reaction, theexcess of sodamide is decomposed by the addition of a small amount ofalcohol. Thereaction mass is then filtered with suction, the filtrateevaporated to dryness and the residue is recrystallized from ethylacetate. In this manner there is obtainedlO-(B-dirnethylamino-ethyl)-11- oxo-dibenzo-[bzf]-thia-[1]-aza [4]cycloheptadiene- [2:6] of the formula O ll (l in the form of colorlesscrystals melting at 139-140 C. The colorless hydrochloride obtained inthe manner described in Example 1 melts at 232235 C. and is easily.soluble in Water.

In the above reaction the dioxane may be replaced by another inertsolvent such as benzene, toluene or xylene.

EXAMPLE 3 22.7 parts of 1l-oxo-dibenzo-[b:f]-thia-[1]-aza-[4]-cycloheptadienc-[2t6] and 5 parts of sodamide are heated with 250 partsby volume of dioxane for 90 minutes at the boil. There is then added inthe course of one hour a solution of 18.7 parts of'y-diethylamino-propyl chloride in dioxane at the boiling temperatureand boiled for a further 2 hours. The excess of sodamide is thendecomposed with a small amount of alcohol, the reaction mixture isfiltered with suction and the filtrate is evaporated to dryness. Theresidue is dissolved in dilute hydrochloric acid, a small amount ofneutral substances is extracted from this solution with ether, and thebase so obtained is precipitated from the acid solution by means ofalkali. This base is taken up in ether and the ether is distilled off,after drying the solution over potassium carbonate. The residual oil isdistilled in a high vacuum, whereby-(y-diethylamino-propyl)-l1oxo-dibenzo-[b:f]-thia-[1]-aza-[4]-cycloheptadiene-2 6] of the formula passes over in the form of a yellowish thick oilboiling at 182-188 C. under apressure of 0.18 mm.

The hydrochloride obtained in ethyl acetate with the aid of alcoholichydrochloric acid is a. colorless crystalline powder melting at 148-150C., which is easily soluble in water.

EXAMPLE 4 In the procedure described in Example 2 there is used, insteadof B-dimethylaminoethyl chloride, 18.2 parts of 'y-pyrrolidino-propylchloride. After working up the dioxane solution as described in Example2, there is obtained a crude base which is recrystallized from threetimes the quantity of isopropyl ether to yeld pure 10-(v-pyrrolidinopropyl) -11- oxo dibenzo- [bzf] thia [l] aza [4]-cycloheptadiene-[Z 6] of the formula CHzCHr-CH1N in the form ofcolorless crystals melting at 76-78 C.

The hydrochloride prepared in the same manner as described in Example 1,is recrystallized from a mixture of ethyl acetate and alcohol and meltsat 197-198" C. It is easily soluble in water.

By starting from 'y-piperidino-propyl chloride there can be obtained ina similar manner 10-('y-piperidino-propyl)- 11 oxo dibenzo [b:f] thia[l] aza [4] cycloheptadiene- [2:61 of the formula salt (l EXAMPLE 5 56.7parts of 11-oxo-dibenzo-[b:fl-thia-[ll-aza-[41- cycloheptadiene-[2z6]are heated at the boil with 12.5 parts of sodamide in 550 parts ofdioxane until the evolution of ammonia ceases. A dioxane solution of38.0 parts of fl-dimethylamino-a-methyl-ethyl chloride is introduceddropwise in the course of minutes, and then the whole is heated at theboil for a further 2 hours.

- When the reaction has ceased, a small amount of methanol is added andthe'warm reaction mass is filtered with suction. The filtrate isevaporated to dryness and the evaporation residue is crystallized from 3parts by volume of hexane, whereby 63 parts of a crystallizate melttingat 106-1 10 C. are obtained. Further recrystallization of this fractionraised the melting point to ll01l2 C. It is 10-(fi-dimethylamino-fi-methyl-ethyl)-ll-oxodi benzo [bzf] thia [ll aza [4]cycloheptadime-[2:6] of the Formula I. A further fraction having a lowermelting point is IO-(B-dimethylamino-amethyl ethyl) 11 oxo dibenzo [b:f]thia [l]- aza-[4]-cycloheptadiene-[2:6] of the Formula H.

o '0 II I from iso-propanol melts at ISO-152 C. It is easily soluble inwater.

EXAMPLE 6 39.3 parts of 8-chloro-1l-oxo-dibenzo-[brf]-thia-[1]-aza-[4]-cycloheptadiene-[2:6], 7.5 parts of sodamide and 375 parts byvolume of dioxane are heated at the boil until the evolution of ammoniaceases. 20.2 parts of B-dimethyl-amino-ethyl chloride are then run in inthe course of one hour, and the whole is heated for a further 2 hoursunder reflux. After the addition of a small amount of methanol, themixture is filtered with suction and the filtrate is evaporated todryness. The dry residue is dissolved in 4 parts by volume ofiso-propylether. Upon cooling, 8 chloro IO-(B-dimethyl-aminoethyl) -11oxo dibenzo [b:f] thia [1] aza [4]- cycloheptadiene-[2z6] of the formula0 II N-C (III I I S separates out in good yield in the form of colorlesscrystals melting at 92-94 C.

The hydrochloride, which is prepared from the base in a mixture of ethylacetate and alcohol with hydrochloric acid, melts at 236238 C., and iseasily soluble in water.

EXAMPLE 7 8 chloro ('y dimethylamino propyl) lloxo dibenzo [bzf] thia[1] aza [4] cycloheptadime-[2:6] of the formula is obtained in the formof colorless crystals melting at Ill-113 C. by the procedure describedin Example 6, by using, instead of fi-dimethylamino-ethyl chloride 30.0parts of 'y-dimethylamino-propyl chloride.

The hydrochloride is prepared from the base by neutralizing a solutionin ethyl acetate with the calculated quantity of alcoholic hydrochloricacid. It melts at 172- 174 C. and dissolves well in Water.

EXAMPLE 8 8 chloro 10 ('y diethylamino propyl) 11 oxo dibenzo [bzf] thia[1] aza [4] cycloheptadiene- [2:61- melting at 51-53 C. is prepared asdescribed in Example 6 by using, instead of fl-dimethylamino-ethylchloride, 28.0 parts of y-diethylamino-propyl chloride.

6 The base can be recrystallized from hexane. It has the followingformula die The hydochloride is obtained by neutralizing a solution ofthe base in isopropanol with the calculated quantity of alcoholichydrochloric acid. It melts at 186-188 C.

EXAMPLE 9 If instead of the 8-chloro-1l-oxo-compound described inExample 6 there are used 39.3 parts of 7-chloro-11- oxo [b:f] thia [1]aza [4] cycloheptadiene- [2:6] there is obtained7-chloro-IO-(B-dimethylaminoethyl) -11- 0x0 dibenzo [bzf] thia [l] aza[4]- cyclo-heptadiene-[2:6]- of the formula CHr-CH2N(C B)2 II -o ascolorless crystals melting at 87-89 C. from iso-propyl ether. Thehydrochloride prepared in ethanol has a melting point of 259-261 C. withdecomposition.

EXAMPLE 10 39.3 parts of7-chloro-1l-oxo-dibenzo-[b:f]-thia-[llazo-[4]-cycloheptadiene-[2:6], 7.5parts of sodamide and 26.4 parts of diethylamino-ethyl chloride indioxane are reacted in the manner described in Example 6. There isobtained7-chloro-IO-(fi-diethylamino-ethyl)-1l-oxo-dibenzo-[bzfl-thia-[l]-aza--[4]cycloheptadiene [2:6] of the formula as a thick oil boiling at 190-193C. under 0.17 mm. pressure of mercury. With dilute hydrochloric acid thesomewhat difi-lcultly soluble hydrochloride melting at 232-235 C. withdecomposition is obtained. The methane sulfonate, which is prepared inethylacetateether, melts at 98 C. It is easily soluble in water.

EXAMPLE 1 1 Nil . S in the form of colorless crystals melting at 113-115C. The hydrochloride prepared in ethyl acetate by the addition of thecalculated quantity of alcoholic hydrochloric acid is a colorlesscrystalline powder melting at 182-184 C.

EXAMPLE 12 If instead of 8-chloro-11-oxo-dibenzo-[b:f]-thia-[1]-aza-[41-cycloheptadiene-[2:6] as in Example 6,6-chloroll-oxo-dibenzo-[bzf] -thia-[1]-aza-[4] cycloheptadiene- [2:6] isused, there is obtained the6-chloro-10-(fl-dimethylamino-ethyl)-1l-oxo-dibenzo-[b:f]thia-[1] aza'[4]-cycloheptadiene-[2:6l of theformula otrrcmmoum as colorless crystalsmelting at 98400 C. (from isopropyl ether). The hydrochloride which isprepared in alcohol-ethyl acetate, is a colorless crystalline powdermelting at 242 C. With decomposition.

EXAMPLE 13 as colorless crystals melting at l081l0 C. (from iso propylether). The hydrochloride prepared in the manner described in Example 7melts at 123-126" C.

EXAMPLE 14 If instead of the 39.3 parts of 8-chloro-1l-oxo-dibenzo-[b:f]-thia-[ll-aza-[4]-cycloheptadiene-[2:6] as in Example 6, 36.3 partsof the S-amino compound are used, there is obtained the8-amin0-l0-(fi-dimethylamino ethyl)=l 1 oxo dibenzo-[bzf]-thia [11 aza[4] cycloheptadiene-[2:6] of the formula as faintly yellow crystals(from ethyl acetate) melting 5t l83-186 C. The hydrochloride, which isprepared in alcohol-ethyl acetate, yields crystals melting at 204 C. Itis soluble in water.

EXAMPLE 15 obtained the 7,8 dichloro-IO-('y-dimethylamino-propyl)1l-oxo-dibenzo-[b:f]-thia-[1]-aza-[4] cycloheptadiene- [2:61 of theformula as colorless crystals melting at 9395 C. (from ether). Thehydrochloride which is prepared in alcohol, has a melting point of234236 C.

EXAMPLE 16 If instead of the S-chloro-compound as in Example 6, 392parts of Z-chloro-ll-oXo-dibenzo-[b:f]-thia-[ll-aza-[4]-cycloheptadiene-[2:6] are used, there is obtained 2-chloro-lO-(B-dimethylamino ethyl) ll oxo dibenzo- [bzfl-thia-[l] aza [4]cycloheptadiene [2:6] of the formula N-o i s as a practically colorlessoil boiling at ISO- C. under 0.2 mm. pressure of mercury. Thehydrochloride, prepared by the addition of alcoholic hydrochloric acidmelts at 230 C.

EXAMPLE 17 19 parts of S-chloro-(y-diethylamino-propyl)-1l-oxodibenzo[bzf] thia [l] aza [4] cycloheptadiene- [2:6] and 9 parts of ethyliodideare refluxed in 200 parts by volume of ethylacetate for 1 hour. Aftersome time crystals begin to appear. When the precipitation is complete,the crystals are removed by filtration. The 8 chloro 10 ('ytriethylammino propyl) l1 oxo dibenzo [bzf] thia [1] aza [4]cycloheptadiene- [2:6]-iodide of the formula GH -CHr-C-HnllKC2H5):

melts at 2l22l4.

The starting materials for the foregoing examples are prepared asfollows:

Example A 129.5 parts of Z-amino-diphenylsulfide-Z-carboxylic acidmethyl ester are heated in a bath having a temperature of 245-250 C. for40 minutes while distilling off the methyl alcohol formed and for afurther 40 minutes under reduced pressure at the same temperature. Inthis manner the melt becomes solid. After being cooled, the crystallinemass is extracted at the boil with ethanol, disintegrated and filteredwith suction in the cold. There is obtained in very good yieldll-oxo-dibenzo-[bzf]-thialll aza-[4]-cycloheptadiene-[2:6] of theformula H 0 1 II NG s in the form of colorless crystals melting at257-259 C. The new compound can be recrystallized from glacial aceticacid or methyl ethyl ketone.

The reaction period can be considerably shortened by increasing thetemperature to 280 C. Instead of the methyl ester there may be use]another ester, for example the ethyl or propyl ester.

Example B in the form of colorless crystals melting at 294-298 C whichcan be recrystallized from dimethylformamide.

The 2 amino 4 chloro diphenyl sulfide 2 carboxylic acid methyl esterused as starting material in this example may be prepared, for example,by introducing 2,5-dichloro-nitrobenzene into a boiling solution ofsodium thiosalicyclic acid methyl ester in methanol in the presence of acopper catalyst, and then reducing the resulting nitro-compound forexample, catalytically. It melts at 136-137 C.

Example C 24.5 parts of 2-amino-diphenyl-sulfide-Z-carboxylic acid areheated for 3060 minutes in an oil bath at ISO-200 C. The resultingll-oxo-dibenzo-[b:f]-thia- [1]aza[4]-cycloheptadiene-[2:6] melting at257-259 C. is identical with the compound obtained in Example A. ExampleD If in Example B, Z-amino-5-chloro-diphenyl-sulfide-Z'- carboxylic acidmethyl ester is used in the place of the 2-amino-4-chloro-compound,there is obtained 7-chloro- 11 oxo dibenzo [bzf] thia [1] aza [4]cycloheptadiene-[2:6] of the formula as colorless crystals melting at3l6320 C. (crystallized from dimethyl formamide The above startingmaterial can be obtained for example, by reacting2,4-dichloro-nitrobenzene with a solution of sodium thiosalicylic acidmethyl ester in methanol at 40 65 C. and then reducing catalytically inthe presence of Raney nickel the resulting nitro-compound melting at90-93 C. The 2-amino-5-chloro-diphenyl-sulfide- 2'-carboxylic acidmethyl ester melts at l44l46 C.

In an analogous manner there is obtained from 2- amino 6 chloro diphenylsulfide 2 carboxylic acid methyl ester melting at l24l26 C. 6-chloro-lloxo dibenzo [bzf] thia [1] aza [4] cycloheptadime-[2:6] of the formulamelting at 288-290 C. as a colorless crystalline powder tfrom dimethylformamide).

'10 Example E 29.4 parts of 2-amino-diphenyl-sulfide-4'-chloro 2'-carboxylic acid methyl ester are heated for one hour in an oil bathhaving a temperature of 230-260 C. in

vacuo. After cooling, the reaction mass is boiled with 1 methanol,disintegrated and filtered. There is obtained2-chloro-1lroxo-dibenzo-['b:f]-thia-[1]-aza [4] cyclohe'ptadiene-[2z6]of the formula i ii 0 E I I :TO]

as almost colorless crystals which can be recrystalllzed from dimethylformamide. It melts at 250-252 C.

The 2 amino-diphenyl-sulfide-4'-chloro-2-carboxylic acid methyl esterused as starting material can be prepared for example, by heatingortho-chloro-nitrobenzene with 5-chloro-thiosalicylic acid methyl esterin methanol in the presence of the calculated quantity of sodiummethylate and reducing the resulting nitro compound catalytically withRaney nickel; it melts at 98-100 C.

Example F 32.8 parts of 2-amino-4,5-dichloro-diphenyl-sulfide-2'-carboxylic acid methyl ester are reacted according to the directionsgiven in Example B. There is obtained 7,8- dichloro 11 oxo[b:-f]-thia-[1]-aza-[41-cycloheptadime-[2:6] of the formula as colorlesscrystals melting at 301304 C.

The above starting material is obtained by reacting2,4,5-trichloro-nitrobenzene with the sodium salt ofmethylthiosalicylate in methanol at 40 to 65 C. in the presence ofcopper powder and catalytically reducing with Raney nickel the nitrocompound thus obtained, which melts at 146-148 C.

EXAMPLE 18 28 grams of 8-methyl-1l-oxo-dibnzo-[bzfl-thia-[1]-aza-[4]-cycloheptadiene-[2:6] and 6.4 grams of sodamide are heated in300 cc. of absolute dioxane for 3 hours to boiling until the evolutionof ammonia subsides. Then the whole is cooled to 60 C., treated dropwisewith stirring within 30 minutes with a solution of 22.4 grams ofB-dimethylaminoethyl chloride in- 60 cc. of absolute benzene and thewhole heated with stirring for a further 3 hours to boiling. Filtrationis carried out from deposited common salt, followed by evaporation undervacuum and taking up of the residue in 200 cc. of ether. The etherealsolution is extracted with dilute hydrochloric acid and the aqueoussolution treated with alkali. The separated base is dissolved in etherand the ether solution dried over magnesium sulfate and evaporated. Thesolid residue is recrystallised from isopropanol-petroleum ether and inthis manner 33 grams are obtained of 8- methyl l0 (,8dimethylamino-ethyD-ll-oxo-dibenzo-[b:f]-thia-[IJ-aza-[4]-cyc1oheptadiene-[2:6] of the formula N-ii in theform of colorless crystals of M. P. 109-110 C.

A solution of the base in ethyl acetate gives by the addition of thecalculated quantity of alcoholic hydrochlo'rie acid, the colorlesshydrochloride of M. P. 223- 225 C. which is easily soluble in water.

In the above reaction, the dioxaue can be replaced by another inertsolvent such as benzene, toluene or xylene.

The 8 methyl-ll-oxo-dibenzo-[bzfl-thia-[l]-aza-[4]-cycloheptadiene-[2:6] used as starting material in this example can beprepared as follows:

In 300 cc. of absolute methanol are dissolved consecutively 17 grams ofsodium and 112 grams of thiosalicyclic acid methyl ester. The solutionproduced is now heated to boiling and treated within minutes with 130grams of 3-nitro-4-chlorotoluene. The whole is then boiled for 2 /2hours under reflux and filtered hot; on cooling, yellow crystalsseparate out. The product is filtered and in this manner 156 gramsobtained of 2- nitro 4 methyl-diphenyl sulphide -2 -carboxylic acidmethyl ester of M. P. 104-106 C.

150 grams of the nitro compound above obtained are dissolved in 1100 cc.of ethyl acetate and hydrogenated with hydrogen in the presence of 70grams of nickel catalyst. After the catalyst has been filtered off, thesolution is evaporated to 250 cc. and on cooling colorless crystalsseparate out. In this manner 125 grams of 2 amino 4 methyl-diphenylsulphide-2'-carboxylic acid methyl ester are obtained of M. P. 83-85 C.

60 grams of the resulting amino compound are heated in a bath at 240270C. for 1 hour while allowing the methyl alcohol produced to distill oiland then for a further 40 minutes under reduced pressure at the sametemperature. As a result the melt becomes solid. After cooling, thecrystal mass is extracted by boiling with 50 cc. of absolute alcohol,triturated and filtered with suction when cold. In this manner 47 gramsare obtained of S-methyll l-oxo-dibenzob f -thia- [-1 l-aza- [4]-cycloheptadiene-[2z6] in the form of colorless crystals of M. P. 228291C.

The new compound can be recrystallized from glacial acetic acid or fromdimethyl formamide.

EXAMPLE 19 EXAMPLE 20 By using, according to the directions of Example18, instead of fi-dimethylamino-ethyl chloride 28.5 grams offi-N-isopropyl-N-methylamino-ethyl chloride and recrystallizing thecrude base obtained from petroleum ether, theS-methyl-10-(B-N-isopropyl-N-methyl-amino ethyl)- ll-oxo-dibenzo-[b:f]-thia-[1]-aza-[4l cycloheptadiene- [2:61 of theformula 0 CH it ll1. l)

is obtained as colorless crystals of M. P. 92-93" C.

The hydrochloride, obtained in ethyl acetate with the aid of alcoholichydrochloric acid, is a colorless crystal 12 powder of M. P. 209-210 C.which is easily soluble in water.

EXAMPLE 21 The S-methyl-IO-(y-dimethylamino propyl) 11 oxodibenzo- [b fl-thia-[ ll-aza- [4] -cycloheptadiene-{2: 6] of the formula is obtainedin the form of colorless crystals of M. P. 83-85" C., using thedirections of Example 18 but with the replacement ofB-dimethylamino-ethyl chloride by 24.5 grams of -dimethylaminopropylchloride.

The hydrochloride, prepared in an alcohol-ethyl acetate mixture has amelting point of 170-172 C.; it is easily soluble in water.

EXAMPLE 22 10 grams of7-methyl-1l-oxo-dibenzo-[b:f]-thia-[llaza-[4]-cycloheptadiene-[2:6] areboiled with 2.3 grams of sodamide in 150 cc. of absolute dioxane for 3hours under reflux with stirring until the evolution of ammoniasubsides. The whole is now cooled to C. and treated dropwise withenergetic stirring, within 30 minutes, with a solution of 8 grams ofB-dimethylamino-ethyl chloride in 40 cc. of absolute benzene. Afterboiling for 3 hours under refiux, the excess of sodamide is destroyedwith a little methyl alcohol, deposited common salt is filtered oif andthe filtrate is evaporated under vacuum to dryness. The residue is takenup in 150 cc. of ethyl acetate, extracted with dilute sulfuric acid andthe aqueous acid solution is treated with alkali. The base produced istaken up in ethyl acetate and after drying over magnesium sulfate thesolvent is distilled off. The residual oil becomes solid on standing andafter recrystallization from ether-petroleum ether the pure7-methyl-10-(fl-dimethylamino-ethyl)-1l-oxo-dibenzo [bzf] -thia [1] aza-[4]-cycloheptadiene-[2:6l of the formula is obtained in colorlesscrystals of M. P. -76 C.

From the base the hydrochloride is obtained by neutralisation of thealcoholic solution with the calculated quantity of hydrochloric acid inethyl acetate. It melts at 236-237 C. and is soluble in water.

The 7-methyl-1l-oxo-dibenzo-[bzfl-thia-tll-aza [4] cycloheptadiene-[2z6]used as starting material in this example is prepared by a processanalogous to that described in Example 18 for theS-methyl-ll-oxo-dibenzo- [bzfl-thia-E ll-aza-[4] -cycloheptadiene- [2:6]

From 3-chloro-4-nitro-toluene and thiosalicyclic acid methyl ester thereis obtained the 2-nitro-5-methyl-diphenyl-sulphide-2-carboxylic acidmethyl ester of M. P. 86-88 C. By catalytic hydrogenation there isobtained therefrom the 2-amino-5-methyl-diphenyl-sulfide-2-carboxylicacid methyl ester of M. P. 82-84 C., which on heating to 240-270 C.gives 7-methyl-11-oxo-dibenzo-[bzfl-thia-Ell-aza-[4]-cycloheptadiene-[2:6] of M. P. 272-274 C.

EXAMPLE 23 By the use of 10 grams of 6-methyl-l1-oxo-dibenzo-[b:fl-thia-tll-aza-[4]-cycloheptadiene-[2:6] instead of the 7-methylcompound of Example 22, there is obtained6-methyl-10-(fi-dimethylamino-ethyl)-l1 oxo dibenzo- [bzf] -thia-[ll-aza- [4] -cycloheptadiene[2 6] of the formula in colorless crystalsof M. P. 105107 C.

The hydrochloride, prepared in an ethanol-ethyl acetate mixture has amelting point of 240241 C. and is soluble in water.

The 6-methyl-1l-oxo-dibenzo-[b:f]-thia-[1]-aza [4]-cycloheptadiene-[2:6] used as starting material in this example isprepared by an analogous process to that described in Example 18 for the8-methyl compound.

Reaction of 2-bromo-3-nitro-toluene with thiosalicyclic acid methylester in the presence of sodium methylate gives the2-nitro-6-methyl-diphenyl-sulphide-2 carboxylic acid methyl ester of M.P. 100102 C., from which, by catalytic hydrogenation, theZ-amino-6-methyl-diphenylsulphide-2'-carboxylic acid methyl ester of M.P. 8687 C. is obtained. Fusion of this amino compound at 240- 270 C.yields the 6-methyl-1l-oxo-dibenzo-ibzfl-thia[1l-aza-[4]-cycloheptadiene-[2:6] of M. P. 257-258 C.

EXAMPLE 24 Lt m /ID as colorless crystals of M. P. 114-115 C.

The hydrochloride, prepared in alcohol-ethyl acetate, is a colorlesspowder of M. P. 255257 C. with decomposition.

The above-mentioned starting material can, for example, be prepared asfollows:

By reaction of 1:2-dimethyl-4-nitro-5-chloro-benzene with a solution ofsodium thiosalicylic acid methyl ester in methanol there is obtained the2-nitro-4z5-dimethyldiphenyl-sulfide-Z'-carboxylic acid methyl ester ofM. P. 9395 C. Subsequent catalytic reduction yields the correspondingamino compound of M. P. 130-132" C. and after fusion at 240270 C. thereis obtained the 7:8- dimethyl 11- x0 dibenzo [bzf] thia [1] aza-[4l-cycloheptadiene-[2z6] of M. P. 303305 C.

EXAMPLE 25 15 grams of 8-methoxy-1l-oxo-dibenzo-[bzfJ-thia-E1]-aza-[4]-cycloheptadiene-[2z6] and 3.2 grams of sod amide are heatedunder reflux with stirring in 150 cc. of absolute dioxane until theevolution of ammonia subsides. The whole is then cooled to 60 C.,treated dropwise with energetic stirring within 30 minutes with asolution of 8.5 grams of B-dimethyl-amino-ethyl chloride in 40 c. ofabsolute benzene and the whole heated with stirring for a further 2hours to boiling. After the reaction mixture has stood for a few hoursat room temperature, unused sodamide is destroyed with a littlemethanol, deposited common salt filtered 0E and the filr141 trateevaporated under vacuum and the residue taken up in 200 c. of ether. Theethereal solution is extracted with dilute hydrochloric acid and theaqueous acid solution treated with alkali whereby the base separates asan oil. This is taken up in ether, the solution dried over magnesiumsulfate and the ether evaporated under vacuum. In this manner 15 gramsare obtained of 8-methoxy-10- (B dimethylamino ethyl) 11 oxo dibenzo[b:f]- thia-El]-aza-[4]-cycloheptadiene-[2:6] of the formulaCHzCH2N(CH3)g as a pale brown viscous oil.

A solution of the base in ethyl acetate gives on addition of thecalculated quantity of alcoholic hydrochloric acid the colorlesshydrochloride of M. P. 189-192 C. which is of good solubility in water.

The 8 methoxy 11 oxo dibenzo [bzf] thia-[1]-aza-[4]-cycloheptadiene-[2:6] used as starting material in thisexample is prepared as follows:

By the reaction of 1-methoxy-3-nitro-4-chlorobenzene with thiosalicylicacid methyl ester in methanol in the presence of sodium methylate thereis obtained the 2- nitro-4-methoxy-diphenyl-sulfide-2'-carboxylic acidmethyl ester of M. P. -106 C. From this by catalytic hydrogenation theZ-amino-4-methoXy-diphenyl-sulfide-2'- carboxylic acid methyl ester ofM. P. 134-135 C. is obtained which when heated to 240-270 C. yields 8-methoxy 11 oxo dibenzo [bzf] thia [1] aza- [4]-cycloheptadiene-[2:6] ofM. P. 218219 C.

EXAMPLE 26 By using instead of the B-dimethylamino-ethyl chloride ofExample 25, 10.3 grams of ,B-diethylamino-ethyl chloride, there isobtained the 8-methoxy-10-(B-diethy1 amino ethyl) 11 oxo dibenzo [bzf]thia [1]- aza-[4]-cycloheptadiene-[2z6] of the formula as a pale brownviscous oil.

The hydrochloride, produced in ethyl acetate using alcoholichydrochloric acid, is a colorless crystal powder of M. P. -192 C.; it isof good solubility in water.

EXAMPLE 27 The 8 methoxy 10 ('y dimethylamino propyl)- 11 oxo dibenzo[bzf] thia [1] aza [4] cycloheptadiene-[2:6] of the formula molecule ofwater of crystallisation and is of good solubility in water.

What is claimed is: 1. A member of the group consisting ofcycloheptadienes of the general formula /R1 AN 10 liu 9 C 1 wherein Astands for a lower alkylene radical, R and R represent members selectedfrom the group consisting of lower alkyl, cycloalkyl having to 6 carbonatoms and, when taken together, morpholino and. lower alkylene radicalsforming with the amino nitrogen 21 ring of S to 6 members, and R and Rrepresent, interchangeably, a member of the group consisting ofhydrogen, halogen, amino, lower alkyl, and lower alkoxy substitutents,and therapeutically useful acid addition salts and lower alkylquaternary ammoniumsalts thereof.

2. (6 dimethylamino ethyl) 11 oxo dibenzo-[b:f]-thia-[l]-aza=[4]-cycloheptadiene-[2:6] of the formula:

l- (L I 4. 7 chloro 10 (B dimethylamino ethyl) 11 oxo dibenzo [bzf] thia[1] aza [4] cycloheptadiene-[2z6] of the formula:

ll NC Gil I I 1 S 6. 8 methyl 10 (5 dimethyl amino ethyl) 11 oxo dibenzo[bzf] thia [1] aza [4] cycloheptadiene-[2z6] of the formula:

No references cited.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No.2,852,510 September 16, 1958 Karl Hofi'mann et al.

It is hereby certified that error appears in the printed specificationof the above, numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

Column 1, line 36, for oxyaalkylene read omaalkylene; line 48, forhereto read hetero; column 5, lines 53 to 61, the formula should appearas shown below instead of as in the patentcolumn 6, line 36, for azoread aea; colmnn 8, line 41, for triethylammino read triethylamwnonio.

Signed and sealed this 6th day of J anuary 1959.

[SEAL] Attest:

KARL H. AXLINE, ROBERT C. WATSON, Attesting Oficer. Oommissz'oner ofPatents.

